1. The Field of the Invention
The invention relates to thrombo-resistant compositions for coating gas permeable polymers and to the methods of manufacturing such coatings so that the resulting product remains gas permeable and thrombo-resistant. More particularly, the present invention immobilizes at least one bioactive molecule, such as heparin, to a gas permeable siloxane surface in order to combat at least one blood-material incompatibility reaction.
2. The Prior Art
Over the years, a large number of medical devices have been developed which contact blood. The degree of blood contact varies with the device and its use in the body. For instance, catheters may briefly contact the blood, while implants, such as heart valves and vascular grafts, may contact blood for a number of years. Regardless of the device, blood contact with foreign materials initiates the process of thrombosis, which may be followed by formation of thromboemboli.
Adsorption of proteins is one of the first events to occur when blood contacts a foreign surface. The compositions and conformation of adsorbed proteins influence subsequent cellular responses such as platelet adhesion, aggregation, secretion, complement activation, and ultimately, the formation of cross-linked fibrin and thrombus. Thrombus formation is an obvious and potentially debilitating response to foreign material in contact with blood.
The initial protein layer at the blood-material interface is subject to denaturation, replacement, and further reaction with blood components. During this phase of protein adsorption, adsorbed fibrinogen is converted to fibrin. Fibrin formation is accompanied by the adherence of platelets and possibly leucocytes. The platelets become activated and release the contents of their granules. This activates other platelets, thereby resulting in platelet aggregation.
A thrombus eventually forms from entrapment of erythrocytes (red blood cells) and other blood constituents in the growing fibrin network. Thrombus growth can eventually lead to partial or even total blockage of the vascular channel and/or interference with the function of the device unless the thrombus is sheared off or otherwise released from the foreign surface as an embolus. Unfortunately, such emboli can be as dangerous as blockage of the vascular channel since emboli can travel through the bloodstream, lodge in vital organs, and cause infraction of tissues. Infarction of the heart, lungs, or brain, for example, can be fatal. Therefore, the degree to which the foreign material inhibits thrombus formation, embolization, and protein denaturation is a determinant of its usefulness as a biomaterial.
In the past, the thrombogenicity of biomedical implants has been treated by the administration of systemic anticoagulants such as heparin and warfarin. However, long-term anticoagulation therapy is not advisable due to the risk of hazardous side effects. Moreover, overdose of anticoagulants may cause lethal side reactions, such as visceral or cerebral bleeding. For these reasons, there have been extensive efforts to develop materials which can be used in biomedical devices or implants which can contact blood with minimal or no systemic anticoagulation therapy being necessary to avoid thrombus formation.
Many studies have attempted to produce a nonthrombogenic blood-contacting surface through immobilization of biologically active molecules onto the surface. Such bioactive molecules counteract various blood-material incompatibility reactions.
Surface modification of polymeric materials offers the advantage of optimizing the chemical nature of the blood/polymer interface while allowing a choice of the substrate to be based upon the necessary mechanical properties of the blood-contacting device.
The methods used to immobilize bioactive molecules onto blood-contacting surfaces fall into four general groups: physical adsorption, physical entrapment, electrostatic attraction, and covalent binding.
Surfaces incorporating bioactive molecules by physical adsorption or entrapment beneath the blood-contacting surface exhibit a significant degree of thrombo-resistance. However, depletion of the bioactive molecules into the blood environment causes the surface to rapidly lose its thrombo-resistant character. Entrained molecules diffuse to the surface which, along with physically adsorbed bioactives, are then "leached" from the surface into the blood plasma by mechanical and chemical mechanisms.
Similarly, electrostatically or ionically bound molecules are subject to partitioning and ion exchange between the blood-contacting surface and the electrolyte-rich plasma resulting in depletion. Covalently bound bioactive molecules resist depletion sufficiently to offer a potentially "long term" thrombo-resistant effect.
Numerous studies of covalent attachment of different biomolecules are available. These studies generally involve the covalent attachment of a single bioactive molecule, usually heparin, designed to counteract one aspect of the blood-material incompatibility reactions. Most studies have focused on covalently binding heparin to a blood-contacting surface. Heparin is the most effective anticoagulant in clinical use today. It is a highly sulfonated mucopolysaccharide containing a number of charged functional groups. Heparin enhances the inactivation of thrombin by antithrombin III, thereby inhibiting the conversion of fibrinogen to fibrin.
Most prior attempts to covalently bind heparin to a blood-contacting surface have severely decreased the activity of heparin. For example, heparin coupled to a blood-contacting surface through one of its carboxyl groups may lose up to 90% of its activity. Other systems, claiming covalent attachment of heparin, are actually heparin covalently bound to a coupling molecule which is subsequently ionically bound to the substrate.
Additional problems are encountered when the blood-contacting surface must also be gas permeable. Siloxane polymers are of particular interest in blood gas exchange devices because siloxane polymers not only possess certain inherent thrombo-resistant properties, but siloxane polymers also are gas permeable. However, siloxane polymers are relatively inert and pose a significant obstacle in modifying the surface in order to become more thrombo-resistant.
From the foregoing, it will be appreciated that what is needed in the art are thrombo-resistant compositions and methods which do not inhibit the gas permeability of the blood-contacting surface. Especially needed are methods for conferring thrombo-resistance to siloxane polymers.
It would be another important advancement in the art to provide gas permeable thrombo-resistant compositions and methods in which a bioactive molecule, such as heparin, is covalently bound to the gas permeable blood-contacting surface, thereby eliminating elution of the bioactive molecule into the blood plasma.
It would be a further advancement in the art to provide gas permeable thrombo-resistant compositions and methods in which the bioactive molecules retain their activity after immobilization on the gas permeable blood-contacting surface.
Such gas permeable thrombo-resistant compositions and methods are disclosed and claimed herein.